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Novel telomerase-increasing compound in mouse brain delays the onset of amyotrophic lateral sclerosis.

Eitan E, Tichon A, Gazit A, Gitler D, Slavin S, Priel E - EMBO Mol Med (2012)

Bottom Line: Hence, we and others hypothesized that increasing telomerase expression by pharmaceutical compounds may protect brain cells from death caused by damaging agents.The survival of telomerase-expressing cells (i.e. motor neurons), but not telomerase-deficient cells, exposed to oxidative stress was increased by AGS-499 treatment, suggesting that the AGS-499 effects are telomerase-mediated.Therefore, a controlled and transient increase in telomerase expression and activity in the brain by AGS-499 may exert neuroprotective effects.

View Article: PubMed Central - PubMed

Affiliation: The Shraga Segal Department of Immunology and Microbiology, Ben-Gurion University of the Negev, Beer-Sheva, Israel.

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AGS-499 increases the survival of NSC-34 cells exposed to oxidative stress in a telomerase-dependent mannerTERT protein expression was examined in vehicle-treated and AGS-499 treated (200 nM) NSC-34, NSC-34TERT-GFP, NSC-34shRNA68 and NSC-34shRNA72 cells for 4 h.Cells were exposed to various H2O2 concentrations for 4 hrs (B) and AGS-499(50 nM or 200 nM) was added (C,D). The medium was replaced by fresh serum-containing medium for 24 hrs. Cell viability was examined by XTT assay (B–D).Represent the effect of H2O2 without AGS treatment. The results are mean ± s.e.m., Two Way ANOVA test p = *10.0017, *20.002, *30.000 compared to none-transfected cells.Treatment of NSC-34 cells only with AGS-499. The results are fold of vehicle (0 µM-H2O2), mean ± s.e.m., Two Way ANOVA test p = *10.045, *20.003 relative to vehicle.The increase in cell survival by AGS-499 (200 nM) in NSC-34, NSC-34TERT-GFP, NSC-34shRNA68 and NSC-34shRNA72 cells calculated as follow: (% of cells treated with AGS/% of vehicle treated cells) − 1. Shown are mean ± s.e.m., n = 5 independent experiments. Two Way ANOVA p = *10.0018, *20.02, *30.006.
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fig09: AGS-499 increases the survival of NSC-34 cells exposed to oxidative stress in a telomerase-dependent mannerTERT protein expression was examined in vehicle-treated and AGS-499 treated (200 nM) NSC-34, NSC-34TERT-GFP, NSC-34shRNA68 and NSC-34shRNA72 cells for 4 h.Cells were exposed to various H2O2 concentrations for 4 hrs (B) and AGS-499(50 nM or 200 nM) was added (C,D). The medium was replaced by fresh serum-containing medium for 24 hrs. Cell viability was examined by XTT assay (B–D).Represent the effect of H2O2 without AGS treatment. The results are mean ± s.e.m., Two Way ANOVA test p = *10.0017, *20.002, *30.000 compared to none-transfected cells.Treatment of NSC-34 cells only with AGS-499. The results are fold of vehicle (0 µM-H2O2), mean ± s.e.m., Two Way ANOVA test p = *10.045, *20.003 relative to vehicle.The increase in cell survival by AGS-499 (200 nM) in NSC-34, NSC-34TERT-GFP, NSC-34shRNA68 and NSC-34shRNA72 cells calculated as follow: (% of cells treated with AGS/% of vehicle treated cells) − 1. Shown are mean ± s.e.m., n = 5 independent experiments. Two Way ANOVA p = *10.0018, *20.02, *30.006.

Mentions: To directly examine the effect of the AGS compound on motor neuron survival after insult, we used the NSC-34 cell line, a common in vitro model for motor neuron-like cells (Matusica et al, 2008). Consistent with our previous results, the AGS compound increased telomerase expression and activity in these cells (Fig 9A, lanes 3 and 4, and Supporting information Fig 2A and B). NSC-34 cells were transfected with hTERT-GFP vector (NSC-34hTERT-GFP; Fig 9A, lane 1) and two TERT shRNA vectors (NSC-34shRNA69, NSC-34shRNA72), which reduced TERT expression and activity. NSC-34shRNA69 exhibited a 73% decrease in TERT expression, while NSC-34shRNA72 exhibited a 54% decrease (Fig 9A, lanes 5 and 7, and Supporting information Fig 2C). AGS treatment did not increase TERT expression in the shRNA-transfected cells but increased the expression of the endogenous TERT in NSC-34hTERT-GFP cells (Fig 9A).


Novel telomerase-increasing compound in mouse brain delays the onset of amyotrophic lateral sclerosis.

Eitan E, Tichon A, Gazit A, Gitler D, Slavin S, Priel E - EMBO Mol Med (2012)

AGS-499 increases the survival of NSC-34 cells exposed to oxidative stress in a telomerase-dependent mannerTERT protein expression was examined in vehicle-treated and AGS-499 treated (200 nM) NSC-34, NSC-34TERT-GFP, NSC-34shRNA68 and NSC-34shRNA72 cells for 4 h.Cells were exposed to various H2O2 concentrations for 4 hrs (B) and AGS-499(50 nM or 200 nM) was added (C,D). The medium was replaced by fresh serum-containing medium for 24 hrs. Cell viability was examined by XTT assay (B–D).Represent the effect of H2O2 without AGS treatment. The results are mean ± s.e.m., Two Way ANOVA test p = *10.0017, *20.002, *30.000 compared to none-transfected cells.Treatment of NSC-34 cells only with AGS-499. The results are fold of vehicle (0 µM-H2O2), mean ± s.e.m., Two Way ANOVA test p = *10.045, *20.003 relative to vehicle.The increase in cell survival by AGS-499 (200 nM) in NSC-34, NSC-34TERT-GFP, NSC-34shRNA68 and NSC-34shRNA72 cells calculated as follow: (% of cells treated with AGS/% of vehicle treated cells) − 1. Shown are mean ± s.e.m., n = 5 independent experiments. Two Way ANOVA p = *10.0018, *20.02, *30.006.
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fig09: AGS-499 increases the survival of NSC-34 cells exposed to oxidative stress in a telomerase-dependent mannerTERT protein expression was examined in vehicle-treated and AGS-499 treated (200 nM) NSC-34, NSC-34TERT-GFP, NSC-34shRNA68 and NSC-34shRNA72 cells for 4 h.Cells were exposed to various H2O2 concentrations for 4 hrs (B) and AGS-499(50 nM or 200 nM) was added (C,D). The medium was replaced by fresh serum-containing medium for 24 hrs. Cell viability was examined by XTT assay (B–D).Represent the effect of H2O2 without AGS treatment. The results are mean ± s.e.m., Two Way ANOVA test p = *10.0017, *20.002, *30.000 compared to none-transfected cells.Treatment of NSC-34 cells only with AGS-499. The results are fold of vehicle (0 µM-H2O2), mean ± s.e.m., Two Way ANOVA test p = *10.045, *20.003 relative to vehicle.The increase in cell survival by AGS-499 (200 nM) in NSC-34, NSC-34TERT-GFP, NSC-34shRNA68 and NSC-34shRNA72 cells calculated as follow: (% of cells treated with AGS/% of vehicle treated cells) − 1. Shown are mean ± s.e.m., n = 5 independent experiments. Two Way ANOVA p = *10.0018, *20.02, *30.006.
Mentions: To directly examine the effect of the AGS compound on motor neuron survival after insult, we used the NSC-34 cell line, a common in vitro model for motor neuron-like cells (Matusica et al, 2008). Consistent with our previous results, the AGS compound increased telomerase expression and activity in these cells (Fig 9A, lanes 3 and 4, and Supporting information Fig 2A and B). NSC-34 cells were transfected with hTERT-GFP vector (NSC-34hTERT-GFP; Fig 9A, lane 1) and two TERT shRNA vectors (NSC-34shRNA69, NSC-34shRNA72), which reduced TERT expression and activity. NSC-34shRNA69 exhibited a 73% decrease in TERT expression, while NSC-34shRNA72 exhibited a 54% decrease (Fig 9A, lanes 5 and 7, and Supporting information Fig 2C). AGS treatment did not increase TERT expression in the shRNA-transfected cells but increased the expression of the endogenous TERT in NSC-34hTERT-GFP cells (Fig 9A).

Bottom Line: Hence, we and others hypothesized that increasing telomerase expression by pharmaceutical compounds may protect brain cells from death caused by damaging agents.The survival of telomerase-expressing cells (i.e. motor neurons), but not telomerase-deficient cells, exposed to oxidative stress was increased by AGS-499 treatment, suggesting that the AGS-499 effects are telomerase-mediated.Therefore, a controlled and transient increase in telomerase expression and activity in the brain by AGS-499 may exert neuroprotective effects.

View Article: PubMed Central - PubMed

Affiliation: The Shraga Segal Department of Immunology and Microbiology, Ben-Gurion University of the Negev, Beer-Sheva, Israel.

Show MeSH
Related in: MedlinePlus